Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome

Background A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. Methods We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. Results All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. Conclusion These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.Genetics of disease, diagnosis and treatmen

Densification of Ni and TiAl by SPS: kinetics and microscopic mechanisms

International audienceDensification by spark plasma sintering (SPS) of ductile (Ni) and brittle (TiAl) metallic materials have been studied to elucidate the mechanism of densification in the two cases. Isothermal densification experiments were carried out to determine the activation parameters in Ni. Transmission electron microscopy (TEM) observations of thin foils extracted by focused ion beam (FIB) in the contact regions between particles of TiAl and Ni powders are presented. Macroscopically, the most striking feature observed here is that the densification of Ni takes place in the wide temperature range of 0.2-1.0 Tm, whereas that of TiAl varies in 0.7-0.9 Tm, which is significantly narrower (Tm being the melting temperature of Ni and the peritectic temperature of TiAl). In Ni, the low activation energy (164 ± 30 kJ/mol), the high dislocation density in the inter-particle contact region, and the formation of recovery cells involving dislocation climb, indicate that the rate-controlling mechanism is probably self-diffusion in dislocations. In TiAl, high dislocation densities leading to reorganization into sub-boundaries point to dislocation climb mechanisms, which are kinetically controlled by volume diffusion. The difference in densification kinetics between Ni and TiAl is then accounted for in terms of the difference in their respective rate-controlling mechanisms operative during densification